The long-term goal of this project is to assemble a critical mass of faculty whose expertise in cell biology, molecular biology and chemistry will be applied to the development of safe and effective AIDS therapeutic drugs. For the past decade, a great deal of research activity has focused upon combating HIV, the causative agent of AIDS. However, few effective anti-retroviral drugs have been approved for clinical use due to dose- dependent toxicity and drug resistance. Therefore, this project will attack the problem of the development of AIDS drugs by: determining the mechanism(s) of action and toxicity of currently used drugs (nucleosides and thalidomide); studying the biochemical and functional characteristics of regulatory proteins (Nef and Tat); developing strategies that combine nucleosides with drugs that target HIV regulatory proteins. This is a multi-investigator project which will be coordinated by Dr. Taylor (Activity Leader) and the faculty involvement will be as follows: 1) Dr. Taylor will perform the studies on anti-viral nucleosides and thalidomide; 2) Dr. Samuel will focus on characterizing the interaction of the HIV protein Nef with human lymphoblastic cells; 3) Dr. Walls will perform the studies on the biochemistry and function of Tat protein; 4) Drs. Taylor, Samuel and Walls will collaborate on the development of a combination regimen. We feel these approaches will supply important knowledge that can be applied to the design of future AIDS therapeutic regimens.